This invention relates to the use of benzamides and nicotinamides, and analogs of this class of compounds such as the N-substituted benzamides and nicotinamides, as anti-inflammatory agents, and to compositions for such use.
The benzamide and nicotinamide analogs are known to possess a wide variety of pharmacological properties including clinical usefulness as anti-arrhythmics, anti-emetics, anti-psychotics, local anaesthetics and radio- and chemosensitizers (Stanley and Rotrosen (eds.), The Benzamides: Pharmacology, Neurobiology and Clinical Aspects, Raven Press, New York, 1982; Horsman, Acta Oncologica 34: 571-587, 1995; Harrington, Drugs 25: 451-494, 1983; Pero et al, Cancer Detection and Prevent., submitted, 1997). These diverse pharmacological properties have been attributed to effects on receptor high affinity binding of signal transducing agents (King and Sanger, Drugs of the Future 14: 875-889, 1989; Olsson et al, Biochem. Pharmacol. 45: 1191-1200, 1993), blood flow (Horsman, Acta Oncologica 34: 571-587, 1995), or inhibited DNA repair and DNA damage accumulation (Pero et al, Biochimie 77: 385-93, 1995; Pero et al, Cancer Detection and Prevent., submitted, 1997; Olsson et al, Carcinogenesis 16: 1029-1035, 1995; Olsson et al, Brit. J. Cancer 74: 368-373, 1996). None of these varied modes of action that so far have been identified with the benzamides or nicotinamides are known to be involved with the pharmacological property of anti-inflammation.
For more than 25 years, it has been indicated in the literature that pyridinyl-N-substituted benzamides have anti-inflammatory properties (Moragues et al, Quim. Ind. (Madrid) 17: 104, 1971; Robert-Piessard et al, Eur. J. Med. Chem. 25: 9-19, 1990). Moreover, it has been reported that these benzamide derivatives also possess anti-ulcerogenic and sedative properties (Moffett et al, J. Med. Chem. 14: 963-968, 1971; Piriou et al, Experientia 41: 1409-1410, 1985; Bouhayat et al, J. Med. Chem. 28: 555-559, 1985). However, in all these studies it was taught that the pyridinyl substitution of the carboxamide of benzamide was selectively anti-inflammatory although other tertiary N-substitutions could be tolerated along with the pyridinyl N-substitution without losing anti-inflammatory, anti-ulcerogenic or sedative activities. As a consequence, so far as the present applicants are aware, no other benzamide, N-substituted or not, has ever been tested for anti-inflammatory properties. The fact that the art has not considered to investigate other benzamide analogs for anti-inflammatory effects, but instead has focused on the N-substituted portion of the molecule, is indicative of the non-obviousness of any inference that the benzamide moiety in itself is useful as an anti-inflammatory agent.